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在钙化性主动脉瓣疾病中，Pi 转运体 SLC20A1/Pit1 的高表达通过调节 Akt-1 促进了矿化。

High expression of the Pi-transporter SLC20A1/Pit1 in calcific aortic valve disease promotes mineralization through regulation of Akt-1.

机构信息

Laboratoire d'Études Moléculaires des Valvulopathies (LEMV), Groupe de Recherche en Valvulopathies (GRV), Quebec Heart and Lung Institute/Research Center, Department of Surgery, Laval University, Quebec, Canada.

出版信息

PLoS One. 2013;8(1):e53393. doi: 10.1371/journal.pone.0053393. Epub 2013 Jan 4.

DOI:10.1371/journal.pone.0053393
PMID:23308213
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3537628/
Abstract

The regulation of phosphate (Pi) handling is crucial during calcification of the aortic valve. Gene profiling of Pi transporters revealed that VIC culture expresses SLC201A1/Pit1 and SLC20A2/Pit2. On exposure to a mineralizing medium (2 mM Pi), the expression of Pi transporters in VIC culture is increased several folds, with the highest magnitude for SLC20A1. By using siRNAs, we established that silencing SLC20A1 significantly reduced Pi-induced mineralization of VICs. In human pathological specimens, we found that the expression of SCL20A1 was increased in CAVD tissues compared to control non-mineralized aortic valves. Treatment of VIC culture with Pi promoted the loss of mitochondrial membrane potential (ΔΨm) and cytochrome c release within the cytosol, leading to apoptosis. Inhibition of Pi transporters with phosphonoformic acid (PFA) prevented Pi-mediated apoptosis of VICs. Moreover, we discovered that the level of the Akt-1 transcript is diminished in CAVD tissues compared with control valves. Accordingly, treatment with Pi caused a reduction of the Akt-1 transcript in VIC culture, and treatment with PFA or siRNA against SLC20A1 restored the level of Akt-1. Overexpression of Akt-1 (pCMVAkt-1) prevented both Pi-induced apoptosis and mineralization of VIC culture. These results strongly suggest that overexpression of SLC20A1 promotes apoptosis and mineralization by altering the level of Akt-1.

摘要

在主动脉瓣钙化过程中，磷酸盐（Pi）处理的调节至关重要。Pi 转运体的基因谱分析显示，VIC 培养物表达 SLC201A1/Pit1 和 SLC20A2/Pit2。在暴露于矿化介质（2mM Pi）时，VIC 培养物中 Pi 转运体的表达增加了数倍，其中 SLC20A1 的增幅最大。通过使用 siRNA，我们证实沉默 SLC20A1 可显著减少 Pi 诱导的 VIC 矿化。在人类病理标本中，我们发现 SCL20A1 的表达在 CAVD 组织中比对照非矿化主动脉瓣增加。VIC 培养物中 Pi 的处理促进了线粒体膜电位（ΔΨm）的丧失和细胞溶质中细胞色素 c 的释放，导致细胞凋亡。用膦甲酸（PFA）抑制 Pi 转运体可防止 Pi 介导的 VIC 凋亡。此外，我们发现 Akt-1 转录本的水平在 CAVD 组织中比对照瓣膜降低。因此，Pi 处理导致 VIC 培养物中 Akt-1 转录本减少，而用 PFA 或 SLC20A1 的 siRNA 处理可恢复 Akt-1 的水平。Akt-1 的过表达（pCMVAkt-1）可防止 Pi 诱导的 VIC 培养物凋亡和矿化。这些结果强烈表明，SLC20A1 的过表达通过改变 Akt-1 的水平促进凋亡和矿化。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ae3/3537628/78a8a6c1bf72/pone.0053393.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ae3/3537628/e4213ccf0d81/pone.0053393.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ae3/3537628/8123efdcd3f2/pone.0053393.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ae3/3537628/fcd001d26c6e/pone.0053393.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ae3/3537628/52ea05367fa4/pone.0053393.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ae3/3537628/78a8a6c1bf72/pone.0053393.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ae3/3537628/e4213ccf0d81/pone.0053393.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ae3/3537628/8123efdcd3f2/pone.0053393.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ae3/3537628/fcd001d26c6e/pone.0053393.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ae3/3537628/52ea05367fa4/pone.0053393.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ae3/3537628/78a8a6c1bf72/pone.0053393.g005.jpg

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本文引用的文献

[1]
ATP acts as a survival signal and prevents the mineralization of aortic valve.

J Mol Cell Cardiol. 2012-2-16

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Can J Cardiol. 2007-10

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